This proposal is a renewal resubmission application for R01 DK53591-09 Mapping Genes for NIDDM Nephropathy in African Americans. The results of the first Genome Wide Association Study (GWAS) of African American diabetic nephropathy (performed in our laboratory), the ongoing NIDDK clinical research study, the Family Investigation of Nephropathy and Diabetes (FIND), and other resources will be combined to identify novel diabetic nephropathy genes in African Americans. This will be achieved by carrying out comprehensive genetic analysis of existing datasets, which will be extended by continued recruitment of African American diabetic nephropathy cases. The combined GWAS analysis (2,274 cases, 8,000 controls) will be followed by replication genotyping in up to 3,000 independent cases analyzed with data from 8,000 controls. Ultimately a combined analysis of greater than 5,000 cases and 16,000 controls will be possible. These efforts will lead to a comprehensive laboratory and computational analysis to investigate the genetic architecture of diabetic nephropathy genes. Results of the genetic analysis will be complemented with bioinformatic approaches to identify compelling candidate genes for susceptibility. These loci will be subjected to detailed molecular genetic analysis including resequencing (as appropriate), expression profiling, and motif identification to examine the functional basis of polymorphisms to define a molecular genetic mechanism for their contribution to diabetic nephropathy. Completion of these aims will contribute significantly to improving prediction, prevention, and treatment of this devastating disease that disproportionately affects the African American population.